Pharmaceutical excipient having improved compressibility

ABSTRACT

A microcrystalline cellulose-based excipient having improved compressibility, whether utilized in direct compression, dry granulation or wet granulation formulations, is disclosed. The excipient is an agglomerate of microcrystalline cellulose particles and from about 0.1% to about 20% silicon dioxide particles, by weight of the microcrystalline cellulose, wherein the microcrystalline cellulose and silicon dioxide are in intimate association with each other. The silicon dioxide utilized in the novel excipient has a particle size from about 1 nanometer to about 100 microns. Most preferably, the silicon dioxide is a grade of colloidal silicon dioxide.

This application is a continuation of U.S. patent application Ser. No.10/850,059, filed May 20, 2004; which is a continuation of U.S. patentapplication Ser. No. 10/338,361, filed Jan. 8, 2003; which is acontinuation of U.S. patent application Ser. No. 09/981,319, filed Oct.16, 2001 (now U.S. Pat. No. 6,521,261); which is a continuation of U.S.patent application Ser. No. 09/754,760, filed Jan. 4, 2001 (now U.S.Pat. No. 6,358,533 B2); which is a continuation of U.S. patentapplication Ser. No. 09/438,646, filed Nov. 12, 1999 (now U.S. Pat. No.6,217,909); which is a continuation of U.S. patent application Ser. No.08/992,073, filed Dec. 17, 1997 (now U.S. Pat. No. 6,103,219); which isa continuation of U.S. patent application Ser. No. 08/724,613, filedSep. 30, 1996 (now U.S. Pat. No. 5,725,884); which is a divisional ofU.S. patent application Ser. No. 08/370,576, filed on Jan. 9, 1995 (nowU.S. Pat. No. 5,585,115).

BACKGROUND OF THE INVENTION

The present invention relates to a novel excipient for use in themanufacture of pharmaceuticals, and in particular, solid dosage formssuch as tablets which include one or more active ingredients.

In order to prepare a solid dosage form containing one or more activeingredients (such as drugs) it is necessary that the material to becompressed into the dosage form possess certain physical characteristicswhich lend themselves to processing in such a manner. Among otherthings, the material to be compressed must be free-flowing, must belubricated, and, importantly, must possess sufficient cohesiveness toinsure that the solid dosage form remains intact after compression.

In the case of tablets, the tablet is formed by pressure being appliedto the material to be tabletted on a tablet press. A tablet pressincludes a lower punch which fits into a die from the bottom and a upperpunch having a corresponding shape and dimension which enters the diecavity from the top after the tabletting material fills the die cavity.The tablet is formed by pressure applied on the lower and upper punches.The ability of the material to flow freely into the die is important inorder to insure that there is a uniform filling of the die and acontinuous movement of the material from the source of the material,e.g. a feeder hopper. The lubricity of the material is crucial in thepreparation of the solid dosage forms since the compressed material mustbe readily ejected from the punch faces.

Since most drugs have none or only some of these properties, methods oftablet formulation have been developed in order to impart thesedesirable characteristics to the material(s) which is to be compressedinto a solid dosage form. Typically, the material to be compressed intoa solid dosage form Includes one or more excipients which impart thefree-flowing, lubrication, and cohesive properties to the drug(s) whichis being formulated into a dosage form.

Lubricants are typically added to avoid the material(s) being tablettedfrom sticking to the punches. Commonly used lubricants include magnesiumstearate and calcium stearate. Such lubricants are commonly included inthe final tabletted product in amounts of less than 1% by weight.

In addition to lubricants, solid dosage forms often contain diluents.Diluents are frequently added in order to increase the bulk weight ofthe material to be tabletted in order to make the tablet a practicalsize for compression. This is often necessary where the dose of the drugis relatively small.

Another commonly used class of excipients in solid dosage forms arebinders. Binders are agents which impart cohesive qualities to thepowdered material(s). Commonly used binders include starch, and sugarssuch as sucrose, glucose, dextrose, and lactose.

Disintegrants are often included in order to ensure that the ultimatelyprepared compressed solid dosage form has an acceptable disintegrationrate in an environment of use (such as the gastrointestinal tract).Typical disintegrants include starch derivatives and salts ofcarboxymethylcellulose.

There are three general methods of preparation of the materials to beincluded in the solid dosage form prior to compression: (1) drygranulation; (2) direct compression; and (3) wet granulation.

Dry granulation procedures may be utilized where one of theconstituents, either the drug or the diluent, has sufficient cohesiveproperties to be tabletted. The method includes mixing the ingredients,slugging the ingredients, dry screening, lubricating and finallycompressing the ingredients.

In direct compression, the powdered material(s) to be included in thesolid dosage form is compressed directly without modifying the physicalnature of the material itself.

The wet granulation procedure includes mixing the powders to beincorporated into the dosage form in, e.g., a twin shell blender ordouble-cone blender and thereafter adding solutions of a binding agentto the mixed powders to obtain a granulation. Thereafter, the damp massis screened, e.g., in a 6- or 8-mesh screen and then dried, e.g., viatray drying, the use of a fluid-bed dryer, spray-dryer, radio-frequencydryer, microwave, vacuum, or infra-red dryer.

The use of direct compression is limited to those situations where thedrug or active ingredient has a requisite crystalline structure andphysical characteristics required for formation of a pharmaceuticallyacceptable tablet. On the other hand, it is well known in the art toinclude one or more excipients which make the direct compression methodapplicable to drugs or active ingredients which do not possess therequisite physical properties. For solid dosage forms wherein the drugitself is to be administered in a relatively high dose (e.g., the drugitself comprises a substantial portion of the total tablet weight), itis necessary that the drug(s) itself have sufficient physicalcharacteristics (e.g., cohesiveness) for the ingredients to be directlycompressed.

Typically, however, excipients are added to the formulation which impartgood flow and compression characteristics to the material as a wholewhich is to be compressed. Such properties are typically imparted tothese excipients via a pre-processing step such as wet granulation,slugging, spray drying, spheronization, or crystallization. Usefuldirect compression excipients include processed forms of cellulose,sugars, and dicalcium phosphate dihydrate, among others.

A processed cellulose, microcrystalline cellulose, has been utilizedextensively in the pharmaceutical industry as a direct compressionvehicle for solid dosage forms. Micro-crystalline cellulose iscommercially available under the tradename EMCOCEL® from Edward MendellCo., Inc. and as Avicel® from FMC Corp. Compared to other directlycompressible excipients, microcrystalline cellulose is generallyconsidered to exhibit superior compressibility and disintegrationproperties.

Another limitation of direct compression as a method of tabletmanufacture is the size of the tablet. If the amount of activeingredient is high, a pharmaceutical formulator may choose to wetgranulate the active with other excipients to attain an acceptably sizedtablet with the desired compact strength. Usually the amount offiller/binder or excipients needed in wet granulation is less than thatrequired for direct compression since the process of wet granulationcontributes to some extent toward the desired physical properties of atablet. Thus, despite the advantages of direct compression (such asreduced processing times and costs), wet granulation is widely used inthe industry in the preparation of solid dosage forms. Many of thoseskilled in the art prefer wet granulation as compared to directcompression because this method has a greater probability of overcomingany problems associated with the physical characteristics of the variousingredients in the formulation, thereby providing a material which hasthe requisite flow and cohesive characteristics necessary to obtain anacceptable solid dosage form.

The popularity of the wet granulation process as compared to the directcompression process is based on at least three advantages. First, wetgranulation provides the material to be compressed with better wettingproperties, particularly in the case of hydrophobic drug substances. Theaddition of a hydrophilic excipient makes the surface of a hydrophobicdrug more hydrophilic, easing disintegration and dissolution. Second,the content uniformity of the solid dosage forms is generally improved.Via the wet granulation method, all of the granules thereby obtainedshould contain approximately the same amount of drug. Thus, segregationof the different ingredients of the material to be compressed (due todifferent physical characteristics such as density) is avoided.Segregation is a potential problem with the direct compression method.Finally, the particle size and shape of the particles comprising thegranulate to be compressed are optimized via the wet granulationprocess. This is due to the fact that when a dry solid is wetgranulated, the binder “glues” particles together, so that theyagglomerate in the granules which are more or less spherical.

Due to the popularity of microcrystalline cellulose, pharmaceuticalformulators have deemed it desirable to include this excipient in aformulation which is wet granulated prior to tabletting. Unfortunately,currently-available microcrystalline cellulose does not hold to thetypical principle that the amount of filler/binder needed in wetgranulation is less than that in direct compression. It is known thatthe exposure of the microcrystalline cellulose to moisture in the wetgranulation process severely reduces the compressibility of thisexcipient. The loss of compressibility of microcrystalline cellulose isparticularly problematic where the formulation dictates that the finalproduct will be relatively large in the environment of use. For example,if a pharmaceutical formulator desires to prepare a solid oral dosageform of a high dose drug, and the use of the wet granulation techniqueis deemed necessary, the loss of compressibility of the microcrystallinecellulose dictates that a larger amount of this material may be neededto obtain an acceptably compressed final product. The additional amountof microcrystalline cellulose needed adds cost to the preparation, butmore importantly adds bulk, making the product more difficult toswallow.

The loss of compressibility of microcrystalline cellulose when exposedto wet granulation has long been considered a problem in the art forwhich there has been no satisfactory solution.

Attempts have been made to provide an excipient having highcompressibility, a small bulk (high apparent density), and goodflowability, while being capable of providing satisfactory factorydisintegration of the solid dosage form, which is applicable to wetgranulation as well as to dry granulation and direct compression methodsfor preparation of solid dosage forms.

For example, U.S. Pat. No. 4,159,345 (Takeo, et al.) describes anexcipient which consists essentially of a microcrystalline cellulosehaving an average degree of polymerization of 60 to 375 and obtainedthrough acid hydrolysis or alkaline, oxidative degradation of acellulosic substance selected from linters, pulps and regeneratedfibers. The microcrystalline cellulose is said to be a white cellulosicpowder having an apparent specific volume of 1.6-3.1 cc/g, a reposeangle of 35° to 42°, a 200-mesh sieve residue of 2 to 80% by weight anda tapping apparent specific volume of at least 1.4 cc/g.

In U.S. Pat. No. 4,744,987 (Mehra, et al.), a particulate co-processedmicrocrystalline cellulose and calcium carbonate composition isdescribed wherein the respective components are present in a weightratio of 75:25 to 35:65. The co-processed composition is said to beprepared by forming a well-dispersed aqueous slurry of microcrystallinecellulose and calcium carbonate and then drying the slurry to yield aparticulate product. The combination of these two ingredients is said toprovide a lower cost excipient which has tabletting characteristicssimilar to those of microcrystalline cellulose and which would satisfy aneed for an economical excipient with good performance that is desiredby the vitamin market.

European Patent Application EP 0609976A1 (assigned to Asahi KaseiKabushiki Kaisha) describes an excipient comprising white powderymicrocrystalline cellulose having an average degree of polymerization offrom 100 to 375, preferably from 190 to 210, and an acetic acid holdingcapacity of 280% or more, preferably from 290 to 370%. The excipient issaid to exhibit high compactability and a high rate of disintegrationand is said to be obtained by heat-treating an aqueous dispersion ofpurified cellulose particles, which has a solids content of 40% or lessby weight, at 100° C. or more, followed by drying, or by subjecting anaqueous dispersion of purified cellulose particles having a solidscontent of 23% or less by weight to thin film-forming treatment anddrying the resultant thin film. The excipient is said to possess a highcompressibility, and a good balance of compactability and rate ofdisintegration.

There still remains a need in the industry for a pharmaceuticalexcipient which possesses excellent compressibility whether utilized ina direct compression or wet granulation procedure.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide an excipient whichis useful in a variety of applications, and which may be utilized indirect compression or wet granulation methods.

It is a further object of the present invention to provide an excipientuseful in direct compression methods which has improved compressibilityrelative to microcrystalline cellulose.

It is a further object of the present invention to provide an excipientuseful in wet granulation methods which has improved compressibilityrelative to microcrystalline cellulose.

It is a further object of the present invention to provide afree-flowing excipient which has excellent compressibility propertieswhen utilized in direct compression or wet granulation methods, andwhich furthermore possesses pharmaceutically acceptable disintegrationproperties.

It is a further object of the present invention to provide an improvedmicrocrystalline cellulose excipient in which the microcrystallinecellulose has not been chemically altered, and which has improvedcompressibility relative to “off-the-shelf” commercially availablemicrocrystalline cellulose.

It is a further object of the present invention to provide a soliddosage form which includes one or more active ingredients and theimproved microcrystalline cellulose excipient of the present invention.

It is a further object of the present invention to provide an oral soliddosage form for one or more drugs which is economical to manufacture,which maintains its integrity during storage, and which possessesexcellent disintegration and dissolution properties when exposed, e.g.,to gastrointestinal fluid.

In accordance with the above objects and others which will be obvious tothose skilled in the art, the present invention is directed to anexcipient comprising a particulate agglomerate of coprocessedmicrocrystalline cellulose and from about 0.1% to about 20% silicondioxide, by weight of the microcrystalline cellulose, themicrocrystalline cellulose and silicon dioxide being in intimateassociation with each other, and the silicon dioxide portion of theagglomerate being derived from a silicon dioxide having a particle sizefrom about 1 nanometer (nm) to about 100 microns (μm), based on averageprimary particle size.

In preferred embodiments, the silicon dioxide comprises from about 0.5%to about 10% of the excipient, and most preferably from about 1.25% toabout 5% by weight relative to the microcrystalline cellulose.

In additional preferred embodiments of the invention, the silicondioxide has a particle size from about 5 nm to about 40 μm, and mostpreferably from about 5 nm to about 50 μm.

In preferred embodiments of the present invention, the silicon dioxideis further characterized by a surface area from about 10 m²g to about500 m²/g, preferably from about 50 m²/g to about 500 m²/g, and morepreferably from about 175 m²/g to about 350 m²/g.

The present invention is further directed to an aqueous slurry useful inthe preparation of a compressible excipient useful in dry and wetgranulation formulation methods, comprising a mixture ofmicrocrystalline cellulose and from about 0.1% to about 20% silicondioxide, by weight relative to the microcrystalline cellulose, thesilicon dioxide having a particle size from about 1 nm to about 100 μm.The solids content of the aqueous slurry is from about 0.5% to about25%, by weight, preferably from about 15% to about 20% by weight, andmost preferably from about 17% to about 19% by weight.

The present invention is further directed to a mixture of an activeingredient(s) and an excipient comprising a particulate agglomerate ofcoprocessed microcrystalline cellulose and from about 0.1% to about 20%silicon dioxide, by weight of the microcrystalline cellulose, themicrocrystalline cellulose and silicon dioxide being in intimateassociation with each other, and the silicon dioxide having a particlesize from about 1 nm to about 100 μm. The ratio of active ingredient toexcipient is from about 1:99 to about 99:1, by weight.

The present invention is further directed to a granulate of an activeingredient(s) and the novel excipient described herein, wherein theactive ingredient(s) and excipient have been subjected to a wetgranulation procedure.

The present invention is further directed to a compressed solid dosageform comprising an active ingredient(s) and the novel excipientdescribed herein, wherein the active ingredient(s) and excipient havebeen directly compressed into the solid dosage form or have beensubjected to a wet granulation procedure and thereafter compressed intothe solid dosage form. The compressed solid dosage form provides asuitable immediate release dissolution profile of the activeingredient(s) when exposed to aqueous solutions during in-vitrodissolution testing, and provides a release of drug in an environment ofuse which is considered bioavailable. In further embodiments of theinvention, the dissolution profile of the solid dosage form is modifiedto provide a controlled or sustained release dissolution profile.

The present invention is further directed to a method of maintainingand/or enhancing the compressibility of microcrystalline cellulose. Themethod includes forming an aqueous slurry containing a mixture ofmicrocrystalline cellulose and silicon dioxide having a particle sizefrom about 1 nm to about 100 μm, and drying the slurry to obtainmicrocrystalline cellulose-based excipient particles in which thesilicon dioxide particles have been integrated with the microcrystallinecellulose particles. Within this aspect of the invention, the slurrycontains from about 0.5% to about 25% by weight microcrystallinecellulose, with amounts of from about 15% to about 20% being preferred.Furthermore, the slurry contains from about 0.25% to about 5% by weightsilicon dioxide. The novel excipient described herein is free-flowing,possesses excellent disintegration properties, and importantly, incertain embodiments possesses improved compressibility relative tonormal “off-the-shelf” commercially available microcrystalline cellulosewhen directly compressed. The advantages of the novel excipientdescribed herein are especially realized in pharmaceutical formulationsprepared using wet granulation techniques. When utilized in wetgranulation techniques, the novel excipient surprisingly provides acompressibility which is substantially improved in preferred embodimentsin comparison to the compressibility of normal “off-the-shelf”commercially available microcrystalline cellulose used in wetgranulation and is even comparable to “off-the-shelf” microcrystallinecellulose used in direct compression techniques. In other embodiments,the novel excipient surprisingly provides a compressibility which issubstantially superior to the compressibility of normal “off-the-shelf”commercially available microcrystalline cellulose used in directcompression techniques.

The term “environmental fluid” is meant for purposes of the invention toencompass, e.g., an aqueous solution, or gastrointestinal fluid.

By “sustained release” it is meant for purposes of the invention thatthe therapeutically active medicament is released from the formulationat a controlled rate such that therapeutically beneficial blood levels(but below toxic levels) of the medicament are maintained over anextended period of time, e.g., providing a 12 hour or a 24 hour dosageform.

By “bioavailable” it is meant for purposes of the invention that thetherapeutically active medicament is absorbed from the sustained releaseformulation and becomes available in the body at the intended site ofdrug action.

By “primary particle size” it is meant for purposes of the inventionthat the particles are not agglomerated. Agglomeration is common withrespect to silicon dioxide particles, resulting in a comparativelyaverage large agglomerated particle size.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings are illustrative of embodiments of the inventionand are not meant to limit the scope of the invention as encompassed bythe claims.

FIG. 1 graphically shows a comparison of the tensile strength of tabletsprepared in accordance with the invention and prior art tablets.

FIG. 2 graphically shows a comparison of the tensile strength of APAPcontaining tablets prepared in accordance with the invention and priorart APAP containing tablets.

FIG. 3 graphically shows a comparison of the tensile strength of tabletsprepared in accordance with the invention to contain MCC coprocessedwith diatomaceous earth, tablets containing MCC coprocessed with 2% w/wSiO₂ and prior art tablets prepared to contain only unmodified MCC.

FIG. 4 graphically illustrates a comparison of the tensile strength oftablets prepared using MCC coprocessed with silica gel, tablets preparedwith the novel coprocessed MCC and tablets prepared with MCC alone.

FIG. 5 graphically illustrates a comparison of the tensile strength oftablets prepared using MCC coprocessed with HS 5 grade SiO₂, tabletsprepared using coprocessed MCC-SiO₂ and prior art tablets prepared tocontain only unmodified MCC.

DETAILED DESCRIPTION OF THE INVENTION

Microcrystalline cellulose is a well-known tablet diluent anddisintegrant. Its chief advantage over other excipients is that it canbe directly compressed into self-binding tablets which disintegraterapidly when placed into water. This widely-used ingredient is preparedby partially depolymerizing cellulose obtained as a pulp from fibrousplant material with dilute mineral acid solutions. Following hydrolysis,the hydrocellulose thereby obtained is purified via filtration and theaqueous slurry is spray dried to form dry, white odorless, tastelesscrystalline powder of porous particles of a broad size distribution.Another method of preparing microcrystalline cellulose is disclosed inU.S. Pat. No. 3,141,875. This reference discloses subjecting celluloseto the hydrolytic action of hydrochloric acid at boiling temperatures sothat amorphous cellulosic material can be removed and aggregates ofcrystalline cellulose are formed. The aggregates are collected byfiltration, washed with water and aqueous ammonia and disintegrated intosmall fragments, often called cellulose crystallites by vigorousmechanical means such as a blender. Microcrystalline cellulose iscommercially available in several grades which range in average particlesize from 20 to 200 microns.

Microcrystalline cellulose is water-insoluble, but the material has theability to draw fluid into a tablet by capillary action. The tabletsthen swell on contact and the microcrystalline cellulose thus acts as adisintegrating agent. The material has sufficient self-lubricatingqualities so as to allow a lower level of lubricant as compared to otherexcipients.

Typically, microcrystalline cellulose has an apparent density of about0.28 g/cm³ and a tap density of about 0.43 g/cm³ . Handbook ofPharmaceutical Excipients, pages 53-55.

When utilized in pharmaceutical applications, microcrystalline celluloseis typically used as a tablet binder/diluent in wet granulation anddirect compression formulations in amounts of 5-30% of the formulation,or more. However, it is known to use, more or less microcrystallinecellulose in pharmaceutical products, depending upon the requirements ofthe formulation.

Silicon dioxide is obtained by insolubilizing dissolved silica in sodiumsilicate solution. When obtained by the addition of sodium silicate to amineral acid, the product is termed silica gel. When obtained by thedestabilization of a solution of sodium silicate in such a manner as toyield very fine particles, the product is termed precipitated silica.Silicon dioxide is insoluble in water. Prior to the present invention,silicon dioxide, and in particular colloidal silicon dioxide, was usedmainly as a glidant and anti-adherent in tabletting processes andencapsulation, promoting the flowability of the granulation. The amountof silicon dioxide included in such tablets for those applications isvery limited, 0.1-0.5% by weight. Handbook of Pharmaceutical Excipients,©1986 American Pharmaceutical Association, page 255. This is due in partto the fact that increasing the amount of silicon dioxide in the mixtureto be tabletted causes the mixture to flow too well, causing a phenomenaknown to those skilled in the tabletting art as “flooding”. If themixture flows too well, a varying tablet weight with uneven contentuniformity can result.

Those skilled in the art will appreciate that the name and/or method ofpreparation of the silicon dioxide utilized in the present invention isnot determinative of the usefulness of the product. Rather, aspreviously mentioned, it has been surprisingly discovered that it is thephysical characteristics of the silicon dioxide which are critical. Inparticular, it has been discovered that silicon dioxide having arelatively large particle size (and correspondingly small surface area),such as silica gel, is not useful in the preparation of the improvedmicrocrystalline cellulose products of the invention. The appendedclaims are deemed to encompass all forms of silicon dioxide having anaverage primary particle size from about 1 nm to about 100 μm, and/or asurface area from about 10 m²/g to about 500 m²/g.

The silicon dioxide utilized in the invention is of the very fineparticle size variety. In the most preferred embodiments of theinvention, the silicon dioxide utilized is a colloidal silicon dioxide.Colloidal silicon dioxide is a submicron fumed silica prepared by thevapor-phase hydrolysis (e.g., at 1110° C.) of a silicon compound, suchas silicon tetrachloride. The product itself is a submicron, fluffy,light, loose, bluish-white, odorless and tasteless amorphous powderwhich is commercially available from a number of sources, includingCabot Corporation (under the tradename Cab-O-Sil); Degussa, Inc. (underthe tradename Aerosil); E.I. DuPont & Co.; and W.R. Grace & Co.Colloidal silicon dioxide is also known as colloidal silica, fumedsilica, light anhydrous silicic acid, silicic anhydride, and silicondioxide fumed, among others. A variety of commercial grades of colloidalsilicon dioxide are produced by varying the manufacturing process. Thesemodifications do not affect the silica content, specific gravity,refractive index, color or amorphous form. However, these modificationsare known to change the particle size, surface areas, and bulk densitiesof the colloidal silicon dioxide products.

The surface area of the preferred class of silicon dioxides utilized inthe invention ranges from about 50 m²/gm to about 500 m²/gm. The averageprimary particle diameter of the preferred class of silicon dioxidesutilized in the invention ranges from about 5 nm to about 50 nm.However, in commercial colloidal silicon dioxide products, theseparticles are agglomerated or aggregated to varying extents. The bulkdensity of the preferred class of silicon dioxides utilized in theinvention ranges from about 20 g/l to about 100 g/l.

Commercially available colloidal silicon dioxide products have, forexample, a BET surface area ranging from about 50±15 m²/gm (AerosilOX50) to about 400±20 (Cab-O-Sil S-17) or 390±40 m²/gm (Cab-O-Sil EH-5).Commercially available particle sizes range from a nominal particlediameter of 7 nm (e.g., Cab-O-Sil S-17 or Cab-O-Sil EH-5) to an averageprimary particle size of 40 nm (Aerosil OX50). The density of theseproducts range from 72.0±8 g/l (Cab-O-Sil S-17) to 36.8 g/l (e.g.,Cab-O-Sil M-5). The pH of the these products at 4% aqueous dispersionranges from pH 3.5-4.5. These commercially available products aredescribed for exemplification purposes of acceptable properties of thepreferred class of silicon dioxides only, and this description is notmeant to limit the scope of the invention in any manner whatsoever.

When the novel excipient of the invention utilizes a colloidal silicondioxide, it has been found that the resultant excipient productsurprisingly provides a compressibility which is substantially improvedin preferred embodiments even in comparison to the compressibility ofnormal “off-the-shelf” commercially available microcrystalline celluloseused in direct compression techniques.

In other embodiments of the present invention, it has been discoveredthat the compressibility of microcrystalline cellulose which is wetgranulated is significantly improved by a wider range of silicon dioxideproducts. Thus, in embodiments of the present invention where animprovement in overall compressibility of the microcrystalline cellulose(whether utilized in wet granulation or dry granulation) is notimportant, and the microcrystalline cellulose product is to be subjectedto wet granulation, it has been discovered that the surface area of thesilicon dioxide can be as low as about 50 m²/gm and the average primaryparticle diameter can be as large as about 100 μm. Such silicon dioxideproducts are also deemed to be encompassed within the scope of theinvention.

Both microcrystalline cellulose and silicon dioxide are substantiallywater insoluble. Therefore, the particle size of these ingredients aspresent in the well-dispersed aqueous slurry is directly related to theparticle size of these two ingredients as they were introduced into theaqueous solution. There is no appreciable dissolution of eitheringredient in the aqueous slurry.

After a uniform mixture of the ingredients is obtained in thesuspension, the suspension is dried to provide a plurality ofmicrocrystalline cellulose-based excipient particles having enhancedcompressibility.

In the spray-drying process, the aqueous dispersion of microcrystallinecellulose and silicon dioxide is brought together with a sufficientvolume of hot air to produce evaporation and drying of the liquiddroplets. The highly dispersed slurry of microcrystalline cellulose andsilicon dioxide is pumpable and capable of being atomized. It is sprayedinto a current of warm filtered air, which supplies the heat forevaporation and conveys a dried product to a collecting device. The airis then exhausted with the removed moisture. The resultant spray-driedpowder particles are approximately spherical in shape and are relativelyuniform in size, thereby possessing excellent flowability. Thecoprocessed product consists of microcrystalline cellulose and silicondioxide in intimate association with each other. Magnifications of theresultant particles indicate that the silicon dioxide is integratedwith, or partially coats, the surfaces of the microcrystalline celluloseparticles. When the amount of silicon dioxide including in the excipientis greater than about 20% by weight relative to the microcrystallinecellulose, the silicon dioxide appears to substantially coat thesurfaces of the microcrystalline cellulose particles. The exactrelationship of the two ingredients of the excipients after coprocessingis not presently understood; however, for purposes of description thecoprocessed particles are described herein as including an agglomerateof microcrystalline cellulose and silicon dioxide in intimateassociation with each other. By “intimate association”, it is meant thatthe silicon dioxide has in some manner been integrated with themicrocrystalline cellulose particles, e.g., via a partial coating of themicrocrystalline particles, as opposed to a chemical interaction of thetwo ingredients. The term “intimate association” is therefore deemed forpurposes of the present description as being synonymous with“integrated” or “united”. The coprocessed particles are not necessarilyuniform or homogeneous. Rather, under magnification, e.g., scanningelectron microscope at 500×, the silicon dioxide at the preferredpercent inclusion appears to be an “edge-coating”.

It is most preferred in the present invention that the microcrystallinecellulose and silicon dioxide are coprocessed, resulting in an intimateassociation of these ingredients, rather than being combined, e.g., as adry mixture. In preferred embodiments of the present invention, theaqueous slurry of the microcrystalline cellulose and silicon dioxide areintroduced into the spray dryer as a single aqueous medium. However, itis possible to separately introduce each ingredient into separateaqueous medium which are then combined. Other procedures for combiningthe microcrystalline cellulose and silicon dioxide known to thoseskilled in the art are deemed to be equivalent to the spray-dryingtechnique described above, and are further deemed to be encompassed bythe appended claims.

In certain preferred embodiments of the present invention, thecoprocessing of the microcrystalline cellulose and silicon dioxide isaccomplished by forming a well-dispersed aqueous slurry ofmicrocrystalline cellulose and silicon dioxide, and thereafter dryingthe slurry and forming a plurality of microcrystalline cellulose-basedexcipient particles. Typically, microcrystalline cellulose is firstadded to an aqueous solution so that a slurry or suspension containingfrom about 0.5% to about 25% microcrystalline cellulose in the form ofsolids is obtained. Preferably, the slurry or suspension contains fromabout 15% to 20% microcrystalline cellulose and most preferably fromabout 17% to about 19% microcrystalline cellulose. At this stage, it isoften desirable to adjust the pH of the slurry to about neutral withammonium hydroxide, sodium hydroxide, and mixtures thereof or the like.The suspension is kept under constant agitation for a sufficient time toassure a uniform distribution of the solids prior to being combined withthe silicon dioxide.

At this point, the silicon dioxide is added to the suspension or slurryin amounts ranging from 0.1% to about 20% by weight, based on the amountof microcrystalline cellulose, amounts from about 0.5% to about 10% arepreferred while amounts of from about 1.25% to about 5% by weight areespecially preferred. The silicon dioxide is preferably in colloidalform prior to addition to the MCC slurry. The microcrystalline celluloseand colloidal silicon dioxide are well-dispersed in the slurry orsuspension prior drying and forming the novel particles.

It is preferred that the suspension be dried using spray-dryingtechniques, as they are known in the art. Other drying techniques,however, such as flash drying, ring drying, micron drying, tray drying,vacuum drying, radio-frequency drying, and possibly microwave drying,can also be used. The exact manner in which the suspension is dried isnot believed to be critical for the microcrystalline cellulose/silicondioxide particles to demonstrate enhanced compressibility after wetgranulating.

Depending upon the amount and type of drying, the concentration of themicrocrystalline cellulose and silicon dioxide in the suspension, thenovel compressible particles will have different particle sizes,densities, pH, moisture content, etc.

The particulate coprocessed product of the present invention possessesdesirable performance attributes that are not present when thecombination of microcrystalline cellulose and silicon dioxide arecombined as a dry mixture. It is believed that the beneficial resultobtained by the combination of these two materials is due to the factthat the two materials are intimately associated with each other.

The average particle size of the integrated excipient of the presentinvention ranges from about 10 microns to about 1000 microns. Particlesizes of about 10-500 microns are preferred, particle sizes of about30-250 microns are more preferred and particle sizes of about 40-200microns are most preferred. It will be appreciated by those of ordinaryskill in the art that the drying of the microcrystalline cellulosesilicon dioxide suspension results in a random size distribution of thenovel excipient particles being produced. For example if spray dryingtechniques are used, droplet size, temperatures, agitation, dispersion,air flow, atomizer wheel speed, etc. will effect final particle size.Furthermore, it is within the scope of the invention to sort ormechanically alter the dried particles according to ranges of particlesizes depending upon end uses. The particle size of the integratedexcipient is not narrowly critical, the important parameter being thatthe average size of the particle must permit the formation of a directlycompressible excipient which forms pharmaceutically acceptable tablets.

The novel excipient has a bulk (loose) density ranging from about 0.2g/ml to about 0.6 g/ml, and most preferably from about 0.35 g/ml toabout 0.55 g/ml. The novel excipient has a tapped density ranging fromabout 0.2 g/ml to about 0.6 g/ml, and most preferably from about 0.35g/ml to about 0.55 g/ml. The pH of the particles is most preferablyabout neutral, although granulates having a pH of from about 3.0 toabout 8.5 are possible. The moisture content of the excipient particleswill broadly range from about 0.5% to about 15%, preferably from about2.5% to about 6%, and most preferably from about 3.0% to about 5% byweight.

The angle of repose is a measurement used to determine the flowcharacteristics of a powder. The angle of repose is subject toexperiment and experimenter, but in a comparative test, the novelexcipient is superior.

The novel excipient of the invention is free-flowing and directlycompressible. Accordingly, the excipient may be mixed in the desiredproportion with an active agent and optional lubricant (drygranulation), and then directly compressed into solid dosage forms. Inpreferred embodiments of the present invention wherein the silicondioxide is colloidal silicon dioxide, the novel excipient comprising thecoprocessed microcrystalline cellulose and colloidal silicon dioxideintegrated together represents an augmented microcrystalline cellulosehaving improved compressibility as compared to standard commerciallyavailable grades of microcrystalline cellulose.

Alternatively, all or part of the excipient may be subjected to a wetgranulation with the active ingredient. A representative wet granulationincludes loading the novel excipient particles into a suitablegranulator, such as those available from Baker-Perkins, and granulatingthe particles together with the active ingredient, preferably using anaqueous granulating liquid. The granulating liquid is added to themixture with stirring until the powdery mass has the consistency of dampsnow and then wet screened through a desired mesh screen, for example,having a mesh from about 12 to about 16. The screened granulate is thendried, using standard drying apparatus such as a convection oven beforeundergoing a final screening. Additional dry screening of this materialis possible, such as by using screens of from about 40 to about 200mesh. Those materials flowing through 40 and 60 mesh screens may befurther ground prior to ultimate tablet formulation. The thus obtainedwet granulate containing novel-excipient is now capable of undergoingtabletting or otherwise placed into a unit dosage form.

In certain preferred embodiments, a portion of the total amount of thenovel excipient is wet granulated with the active ingredient, andthereafter the additional portion of the novel excipient is added to thegranulate. In yet other embodiments, the additional portion of the novelexcipient to be added to the excipient/active ingredient granulate maybe substituted with conventional microcrystalline cellulose, or otherexcipients commonly used by those skilled in the art, depending ofcourse upon the requirements of the particular formulation.

By virtue of the novel excipient of the present invention, the amount ofthe novel excipient compared to the amount of microcrystalline cellulosewhich must be used in a wet granulation technique to obtain anacceptable solid dosage form is substantially reduced.

In other embodiments of the invention, a further material is added tothe slurry of microcrystalline cellulose and silicon dioxide. Suchadditional materials include non-silicon metal oxides, starches, starchderivatives, surfactants, polyalkylene oxides, cellulose ethers,celluloses esters and mixtures thereof. These additives may be includedin desired amounts which will be apparent to those skilled in the art.

In addition to one or more active ingredients, additionalpharmaceutically acceptable excipients (in the case of pharmaceuticals)or other additives known to those skilled in the art (fornon-pharmaceutical applications) can be added to the novel excipientprior to preparation of the final product. For example, if desired, anygenerally accepted soluble or insoluble inert pharmaceutical filler(diluent) material can be included in the final product (e.g., a soliddosage form). Preferably, the inert pharmaceutical filler comprises amono-saccharide, a disaccharide, a polyhydric alcohol, inorganicphosphates, sulfates or carbonates, and/or mixtures thereof. Examples ofsuitable inert pharmaceutical fillers include sucrose, dextrose,lactose, xylitol, fructose, sorbitol, calcium phosphate, calciumsulfate, calcium carbonate, “off-the-shelf” microcrystalline cellulose,mixtures thereof, and the like.

An effective amount of any generally accepted pharmaceutical lubricant,including the calcium or magnesium soaps may optionally be added to thenovel excipient at the time the medicament is added, or in any eventprior to compression into a solid dosage form. The lubricant maycomprise, for example, magnesium stearate in any amount of about 0.5-3%by weight of the solid dosage form.

The complete mixture, in an amount sufficient to make a uniform batch oftablets, may then subjected to tabletting in a conventional productionscale tabletting machine at normal compression pressures for thatmachine, e.g., about 1500-10,000 lbs/sq in. The mixture should not becompressed to such a degree that there is subsequent difficulty in itshydration when exposed to gastric fluid.

The average tablet size for round tablets is preferably about 50 mg to500 mg and for capsule-shaped tablets about 200 mg to 2000 mg. However,other formulations prepared in accordance with the present invention maybe suitably shaped for other uses or locations, such as other bodycavities, e.g., periodontal pockets, surgical wounds, vaginally. It iscontemplated that for certain uses, e.g., antacid tablets, vaginaltablets and possibly implants, that the tablet will be larger.

In certain embodiments of the invention, the tablet is coated with asufficient amount of a hydrophobic polymer to render the formulationcapable of providing a release of the medicament such that a 12 or 24hour formulation is obtained. The hydrophobic polymer which included inthe tablet coating may be the same or different material as compared tothe hydrophobic polymeric material which is optionally granulated withthe sustained release excipient. In other embodiments of the presentinvention, the tablet coating may comprise an enteric coating materialin addition to or instead or the hydrophobic polymer coating. Examplesof suitable enteric polymers include cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate,methacrylic acid copolymer, shellac, hydroxypropylmethylcellulosesuccinate, cellulose acetate trimellitate, and mixtures of any of theforegoing. An example of a suitable commercially available entericmaterial is available under the trade name Eudragit™ L 100-555.

In further embodiments, the dosage form may be coated with a hydrophiliccoating in addition to or instead of the above-mentioned coatings. Anexample of a suitable material which may be used for such a hydrophiliccoating is hydroxypropylmethylcellulose (e.g., Opadry®, commerciallyavailable from Colorcon, West Point, Pa.).

The coatings may be applied in any pharmaceutically acceptable mannerknown to those skilled in the art. For example, in one embodiment, thecoating is applied via a fluidized bed or in a coating pan. For example,the coated tablets may be dried, e.g., at about 60-70° C. for about 3-4hours in a coating pan. The solvent for the hydrophobic polymer orenteric coating may be organic, aqueous, or a mixture of an organic andan aqueous solvent. The organic solvents may be, e.g., isopropylalcohol, ethanol, and the like, with or without water.

The coatings which may be optionally applied to the compressed soliddosage form of the invention may comprise from about 0.5% to about 30%by weight of the final solid dosage form.

In additional embodiments of the present invention, a support platformis applied to the tablets manufactured in accordance with the presentinvention. Suitable support platforms are well known to those skilled inthe art. An example of suitable support platforms is set forth, e.g., inU.S. Pat. No. 4,839,177, hereby incorporated by reference. In thatpatent, the support platform partially coats the tablet, and consists ofa polymeric material insoluble in aqueous liquids. The support platformmay, for example, be designed to maintain its impermeabilitycharacteristics during the transfer of the therapeutically activemedicament. The support platform may be applied to the tablets, e.g.,via compression coating onto part of the tablet surface, by spraycoating the polymeric materials comprising the support platform onto allor part of the tablet surface, or by immersing the tablets in a solutionof the polymeric materials.

The support platform may have a thickness of, e.g., about 2 mm ifapplied by compression, and about 10 μm if applied via spray-coating orimmersion-coating. Generally, in embodiments of the invention wherein ahydrophobic polymer or enteric coating is applied to the tablets, thetablets are coated to a weight gain from about 1% to about 20%, and incertain embodiments preferably from about 5% to about 10%.

Materials useful in the hydrophobic coatings and support platforms ofthe present invention include derivatives of acrylic acid (such asesters of acrylic acid, methacrylic acid, and copolymers thereof)celluloses and derivatives thereof (such as ethylcellulose),polyvinylalcohols, and the like.

In certain embodiments of the present invention, the tablet coreincludes an additional dose of the medicament included in either thehydrophobic or enteric coating, or in an additional overcoating coatedon the outer surface of the tablet core (without the hydrophobic orenteric coating) or as a second coating layer coated on the surface ofthe base coating comprising the hydrophobic or enteric coating material.This may be desired when, for example, a loading dose of atherapeutically active agent is needed to provide therapeuticallyeffective blood levels of the active agent when the formulation is firstexposed to gastric fluid. The loading dose of medicament included in thecoating layer may be, e.g. from about 10% to about 40% of the totalamount of medicament included in the formulation.

The active agent(s) which may be incorporated with the novel excipientdescribed herein into solid dosage forms invention include systemicallyactive therapeutic agents, locally active therapeutic agents,disinfecting agents, chemical impregnants, cleansing agents, deodorants,fragrances, dyes, animal repellents, insect repellents, a fertilizingagents, pesticides, herbicides, fungicides, and plant growth stimulants,and the like.

A wide variety of therapeutically active agents can be used inconjunction with the present invention. The therapeutically activeagents (e.g. pharmaceutical agents) which may be used in thecompositions of the present invention include both water soluble andwater insoluble drugs. Examples of such therapeutically active agentsinclude anti-histamines (e.g., dimenhydrinate, diphenhydramine,chlorpheniramine and dexchlorpheniramine maleate), analgesics (e.g.,aspirin, codeine, morphine, dihydromorphone, oxycodone, etc.),non-steroidal anti-inflammatory agents (e.g., naproxyn, diclofenac,indomethacin, ibuprofen, sulindac), anti-emetics (e.g., metoclopramide),anti-epileptics (e.g., phenyloin, meprobamate and nitrezepam),vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardirine),anti-tussive agents and expectorants (e.g., codeine phosphate),anti-asthmatics (e.g. theophylline), antacids, anti-spasmodics (e.g.atropine, scopolamine), antidiabetics (e.g., insulin), diuretics (e.g.,ethacrynic acid, bendrofluazide), anti-hypotensives (e.g., propranolol,clonidine), antihypertensives (e.g, clonidine, methyldopa),bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone,triamcinolone, prednisone), antibiotics (e.g., tetracycline),antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics,sedatives, decongestants, laxatives, vitamins, stimulants (includingappetite suppressants such as phenylpropanolamine). The above list isnot meant to be exclusive.

A wide variety of locally active agents can be used in conjunction withthe novel excipient described herein, and include both water soluble andwater insoluble agents. The locally active agent(s) which may beincluded in the controlled release formulation of the present inventionis intended to exert its effect in the environment of use, e.g., theoral cavity, although in some instances the active agent may also havesystemic activity via absorption into the blood via the surroundingmucosa.

The locally active agent(s) include antifungal agents (e.g.,amphotericin B, clotrimazole, nystatin, ketoconazole, miconazol, etc.),antibiotic agents (penicillins, cephalosporins, erythromycin,tetracycline, aminoglycosides, etc.), antiviral agents (e.g, acyclovir,idoxuridine, etc.), breath fresheners (e.g. chlorophyll), antitussiveagents (e.g., dextromethorphan hydrochloride), anti-cariogenic compounds(e.g., metallic salts of fluoride, sodium monofluorophosphate, stannousfluoride, amine fluorides), analgesic agents (e.g., methylsalicylate,salicylic acid, etc.), local anesthetics (e.g., benzocaine), oralantiseptics (e.g., chlorhexidine and salts thereof, hexylresorcinol,dequalinium chloride, cetylpyridinium chloride), anti-flammatory agents(e.g., dexamethasone, betamethasone, prednisone, prednisolone,triamcinolone, hydrocortisone, etc.), hormonal agents (oestriol),antiplaque agents (e.g, chlorhexidine and salts thereof, octenidine, andmixtures of thymol, menthol, methysalicylate, eucalyptol), acidityreducing agents (e.g., buffering agents such as potassium phosphatedibasic, calcium carbonate, sodium bicarbonate, sodium and potassiumhydroxide, etc.), and tooth desensitizers (e.g., potassium nitrate).This list is not meant to be exclusive. The solid formulations of theinvention may also include other locally active agents, such asflavorants and sweeteners. Generally any flavoring or food additive suchas those described in Chemicals Used in Food Processing, pub 1274 by theNational Academy of Sciences, pages 63-258 may be used. Generally, thefinal product may include from about 0.1% to about 5% by weightflavorant.

The tablets of the present invention may also contain effective amountsof coloring agents, (e.g., titanium dioxide, F.D. & C. and D. & C. dyes;see the Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 5, pp.857-884, hereby incorporated by reference), stabilizers, binders, odorcontrolling agents, and preservatives.

Alternatively, the novel excipient can be utilized in other applicationswherein it is not compressed. For example, the granulate can be admixedwith an active ingredient and the mixture then filled into capsules. Thegranulate can further be molded into shapes other than those typicallyassociated with tablets. For example, the granulate together with activeingredient can be molded to “fit” into a particular area in anenvironment of use (e.g., an implant). All such uses would becontemplated by those skilled in the art and are deemed to beencompassed within the scope of the appended claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

The examples set forth the preparation of various microcrystallinecellulose/silicon dioxide compositions. Tablets were prepared using eachof the compositions and each of tablet preparations was tested fortensile strength.

Examples 1-3 Preparation of Coprocessed MCC-SiO₂ Compositions andGranulations Thereof Example 1 MCC-SiO₂ Product—5% w/w SiO₂ A. ExcipientParticles

In this example, about 6.2 kilograms of microcrystalline cellulose(MCC), (Mendell Co., Inc. Patterson, N.Y.) in the form of a wet cake wascombined with 5.2 kilograms of water in a mix tank to form a slurrycontaining about 15% solids. The pH was adjusted to about neutral withabout 3 ml of ammonium hydroxide. The slurry was allowed to mix forabout 15 minutes before being combined with 5% w/w silicon dioxide(SiO₂), 200 m²/g (CaboSil, PTG grade, available from Cabot Corp.,Tuscola, Ill.) After allowing the materials to become intimatelycombined, the slurry was spray dried using a Niro Production Minor(Niro, Columbia, Md.), inlet temperature-215° C., outlettemperature-125° C., atomizer wheel speed 22,300 rpm, to provideMCC-SiO₂ having an average particle size of 40-60 microns.

B. Granulation of Excipient Particles

The MCC-SiO₂ particles obtained as a result of step 1 A. were wetgranulated in a Baker-Perkins 10 liter high-sheer granulator for 3minutes using water as the granulating fluid. The resultant product waswet screened through a 12 mesh screen, tray dried in a convection ovenfor about 2-3 hours until a moisture content of less than 5% wasobtained, dry screened and sieved to obtain an average particle size offrom about 55 to about 70 microns.

Example 2 MCC-SiO₂ Product—20% w/w SiO₂

The processes of Example 1A and B were repeated except that 20% w/wsilicon dioxide was used to form the product.

Example 3 MCC-SiO₂ Product—2% w/w SiO₂

In this example, the processes of Example 1A and B were repeated exceptthat 2% w/w silicon dioxide was used to form the product.

Example 4 Dry Blend Mix of MCC and SiO₂ (5% w/w)—Comparative

As a control, EMCOCEL® grade 50 M microcrystalline cellulose (MendellCo., Inc.) and 5% w/w silicon dioxide, 200 m²/g (CaboSil, PTG grade)were dry blended. No spray drying or other treatment of the mixture wasundertaken. The method of Example 1B, however, was repeated.

Example 5 Processed MCC without SiO₂

As a second control, the process described in Example 1B was repeatedexcept that no SiO₂ was added.

Example 6

In this example, batches of compressed tablets were prepared using eachof the products obtained as a result of Examples 1-5. The tablets wereprepared using a Korsch tablet press having a punch size of ⅜″ and anaim weight of about 245 mg. The granulations were included in fiveseparate tabletting runs using compression forces of 6, 12, 18, 24 and30 kN respectively. Ten tablets from each run were weighed, measured fordiameter and tested for thickness and hardness on the Erweka TBH 30tablet hardness tester to determine the compressibility of themicrocrystalline cellulose as measured by tensile strength. The resultsof the analysis are graphically illustrated in FIG. 1 as a comparison oftensile strength versus compression force.

As can be seen from the graph, substantial benefits are obtained bycoprocessing MCC with SiO₂. The tablets prepared using the products ofcomparative examples 4 and 5 demonstrated poor tensile strength. Thenovel excipient is superior and demonstrates approximately the samerelative improvement across the entire range of compression forces.Furthermore, the graph also illustrates that tablets prepared with amere dry admixture of MCC and SiO₂ (example 4 formulation) failed todemonstrate acceptable tensile strengths. Thus, the coprocessed MCC-SiO₂described herein provides significant retention of MCC compressibility.

Examples 7-12

In these examples, compressed tablet products containing 70% by weightMCC and 30% acetaminophen (APAP herein) were prepared. The products ofexamples 7-9 were controls and prepared without the coprocessed MCC-SiO₂of the present invention. The products of examples 10-12, on the otherhand, included 70% by weight of the novel coprocessed MCC-SiO₂ and 30%APAP. Details concerning the preparation of each granulation product isset forth below. A graphical comparison of the tensile strength versuscompression force for each tabletted product is provided in FIG. 2.

Example 7 Intragranulation and Extragranulation of APAP with MCC

In this example, tablets were prepared using off-the-shelf MCC (EMCOCEL®50 M) according to the following formula:

INGREDIENTS WEIGHT (GRAMS) MCC 267.9 APAP 114.8 Deionized water 165.8

One half of the MCC was added to a Baker-Perkins 10 liter blender andcombined with all of the APAP. The blender impeller was adjusted to 200rpm and the chopper was set at 1000 rpm. After one minute, the water wasadded over 90 seconds using a rinse bottle. Thereafter, mixing wascontinued for an additional 90 seconds. The granulation was removed fromthe blender, wet screened through a 12 screen mesh and dried in aconvection oven for 2-3 hours at 60° C. until a moisture content of lessthan 5% was obtained. The granulation was then dry screened through a 16mesh screen before being blended for 10 minutes with the remainingportion of the MCC in a 2 quart V-blender. The granulation was removedfrom the blender and tabletted in accordance with the method describedbelow.

Tablet Strength Testing

In order to prepare tablets for the formulations of examples 7, 8, 10and 11, the following procedure was used: the wet granulation productswere weighed and mixed in a 2 quart V-blender for 5 minutes with 0.2%Pruv™ (sodium stearyl fumarate, available from Mendell Co., Inc.).

Five separate tabletting runs were undertaken with compression forces of5, 10, 15, 20 and 25 kN respectively using a Korsch tablet press havinga punch size of ⅜″ and an aim weight of about 245 mg. Ten tablets fromeach compression force were selected and used in the experiment setforth in Example 13.

Example 8 Wet Granulation of APAP with MCC

In this example, only wet granulation or the intragranulation step asdescribed above was undertaken. The formulation was prepared accordingto the following formula using off-the-shelf EMCOCEL® 50 M MCC:

INGREDIENTS WEIGHT (GRAMS) MCC 178.6 APAP 76.5 Deionized water 170.1

The MCC was added to a Baker-Perkins 10 liter blender and combined withthe APAP. The blender impeller was adjusted to 200 rpm and the chopperwas set at 1000 rpm. After one minute, the water was added over 90seconds using a rinse bottle. Thereafter, mixing was continued for anadditional 90 seconds. The granulation was removed from the blender, wetscreened through a 12 screen mesh and then dried in a convection oven at60° C. for 2-3 hours, until a moisture content of less than 5% wasachieved. The granulation was then dry screened through a 16 mesh screenand tabletted in accordance with the method described in example 7.

Example 9 Direct Compression Formulation of APAP with MCC

A direct compression formulation for tablets was prepared to contain 70%off-the-shelf EMCOCEL® 50 M MCC and 30% APAP by weight. The tablets wereprepared according to the following formula:

INGREDIENTS WEIGHT (GRAMS) MCC 175.0 APAP 74.5 PRUV 0.5

The MCC and APAP were combined in a V-blender and mixed for 15 minutes.Thereafter, the Pruv was added and mixing was continued for another 5minutes. The granulation was removed and five separate tabletting runswere undertaken using compression forces of 5, 10, 15, 20 and 25 kNrespectively on a Korsch tablet press. The tablet press had a punch sizeof ⅜″ and an aim weight of about 245 mg. Ten tablets from eachcompression force were used in the experiment set forth in Example 13.

Example 10 Wet Granulation of APAP with Coprocessed MCC-SiO₂ (5% w/w)

In this example, tablets were prepared by wet granulation with thecoprocessed MCC (5% w/w SiO₂) of Example 1A. The tablet granulation wasprepared according to the following formula:

INGREDIENTS WEIGHT (GRAMS) MCC-SiO₂ 178.6 APAP 76.5 Deionized water170.1

The MCC-SiO₂ was added to a Baker-Perkins 10 liter blender and combinedwith the APAP. The blender impeller was adjusted to 200 rpm and thechopper was set at 1000 rpm. After one minute, the water was added over90 seconds using a rinse bottle. Thereafter, mixing was continued for anadditional 90 seconds. The granulation was removed from the blender, wetscreened through a 12 screen mesh and then dried in a convection ovenfor 2-3 hours at 60° C. until a moisture content of less than 5% wasachieved. The granulation was then dry screened through a 16 mesh screenand tabletted according to the method set forth in Example 7.

Example 11 Intra- and Extragranulation of APAP with MCC-SiO₂ (5% w/w)

A granulation for compressed tablets was prepared according to thefollowing formula:

INGREDIENTS WEIGHT (GRAMS) MCC-SiO₂ 267.9 APAP 114.8 Deionized water165.8

One half of the coprocessed MCC-SiO₂ (prepared as in Example 1A) wasadded to a Baker-Perkins 10 liter blender and combined with all of theAPAP. The blender impeller was adjusted to 200 rpm and the chopper wasset at 1000 rpm. After one minute, the water was added over 90 secondsusing a rinse bottle. Thereafter, mixing was continued for an additional90 seconds. The granulation was removed from the blender, wet screenedthrough a 12 screen mesh and then dried in a convection oven for 2-3hours at 60° C. until a moisture content of less than 5% was achieved.The granulation was then dry screened through a 16 mesh screen beforebeing blended for 10 minutes with the remaining portion of thecoprocessed MCC-SiO₂ in a 2 quart V-blender, removed from the blender,and tabletted according to the method of Example 7.

Example 12 Direct Compression Formulation of APAP with MCC-SiO₂ (5% w/w)

A direct compression formulation similar to that set forth in example 9was undertaken except that the tablets were prepared to contain thecoprocessed MCC-SiO₂ of Example 1A. The tablet granulation was preparedaccording to the following Formula:

INGREDIENTS WEIGHT (GRAMS) MCC-SiO₂ 175.0 APAP 74.5 PRUV 0.5

As was the case in example 9, five separate tabletting runs wereundertaken using compression forces of 5, 10, 15, 20 and 25 kNrespectively on a Korsch tablet press, (punch size: ⅜″ and aimweight—about 245 mg). Ten tablets from each compression force were usedto carry out the experiment set forth in Example 13.

Example 13 Tablet Strength Testing

Ten tablets from each compression force run for each formulationprepared in Examples 7-12 were weighed, measured for diameter and testedfor thickness and hardness on the Erweka TBH 30 tablet hardness testerto determine the compressibility of the microcrystalline cellulose. Theresults are graphically illustrated in FIG. 2 as a comparison tensilestrength versus compression force.

Referring now to FIG. 2, it can be seen that compressed tablets madewith the inventive coprocessed MCC-SiO₂ have relatively high tensilestrengths when compared to those made with off-the-shelf MCC. Theadvantages of the coprocessed MCC-SiO₂ are clearly seen in both directcompression and wet granulation formulations and especially in wetgranulation products.

Examples 14-16 Diatomaceous Earth

In these examples, the coprocessing method described in Example 1A wasrepeated except that diatomaceous earth of about 40 micron particle size(J. T. Baker, Phillipsburg, N.J. was the source of SiO₂).

Example Diatomaceous Earth (wt %) 14 2.0 15 1.0 16 0.5

The resultant granulates prepared according to Example 1B were tablettedaccording to the same method described in Example 6 and evaluated fortensile strength. The products of inventive Example 3 (MCC-SiO₂ 2% w/w)and Example 5 (MCC alone) were included in FIG. 3 for comparisonpurposes.

Referring now to FIG. 3, it can be seen that although the retention ofcompressibility afforded by coprocessing diatomaceous earth is not asgreat as that provided by colloidal SiO₂ having surface areas of about200 m²/g, the co-processed MCC-diatomaceous earth nonethelessdemonstrates improved compressibility in wet granulation formulations.

Examples 17-19 Silica Gel

In these examples, the coprocessing method described in Example 1A wasrepeated using silica gel 200 micron particle size (VWR Corp.,Piscataway, N.J. as the source of SiO₂).

Example Silica Gel (wt %) 17 1 18 2 19 5

The resultant granulates prepared according to Example 1B were tablettedaccording to the same method described in Example 6 and evaluated fortensile strength. The products of inventive Example 3 (MCC-SiO₂ 2% w/w)and Example 5 (MCC alone) were included in FIG. 4 for comparisonpurposes.

Referring now to FIG. 4, it can be seen that the retention ofcompressibility afforded by coprocessing with silica gel is well belowthat provided by colloidal SiO₂ having surface areas of about 200 m²/g.In fact, MCC co-processed with silica gel demonstrates compressibilityproperties about the same as off-the-shelf MCC in wet granulationformulations.

Examples 20-22 HS-5 Grade Silicon Dioxide

In these examples, the coprocessing method described in example 1 wasrepeated using HS-5 grade SiO₂ surface area—325 m²/g (Cabot Corp.,Tuscola, Ill.).

Example Silica Gel (wt %) 20 2 21 1 22 0.5

The resultant granulates prepared according to Example 1B were tablettedaccording to the same method described in Example 6 evaluated fortensile strength. The products of inventive Example 3 (MCC-SiO₂ 2% w/w)and Example 5 (off-the-shelf MCC) were included in FIG. 5 for comparisonpurposes.

Referring now to FIG. 5, the retention of compressibility afforded bycoprocessing with HS-5 is comparable to that obtained using SiO₂ havingsurface areas of about 200 m²/g.

While there have been described what are presently believed to be thepreferred embodiments of the invention, those skilled in the art willrealize that changes and modifications may be made thereto withoutdeparting from the spirit of the invention. It is intended to claim allsuch changes and modifications that fall within the true scope of theinvention.

1-64. (canceled)
 65. A solid dosage form comprising: a compressedmixture of from about 1% to about 99% of an excipient comprising aparticulate agglomerate of coprocessed microcrystalline cellulose andfrom about 0.1% to about 20% by weight silicon dioxide, themicrocrystalline cellulose and silicon dioxide being in intimateassociation with each other, said silicon dioxide portion of saidagglomerate being derived from a silicon dioxide having an averageprimary particle size from about 1 nm to about 100 μm and from about 99%to about 1% of an active agent; and a coating over said compressedmixture.
 66. The solid dosage form of claim 65, wherein the coating is asustained release coating.
 67. The solid dosage form of claim 66,wherein the sustained release coating provides a sustained-release ofthe active agent over a period of at least 12 hours.
 68. The soliddosage form of claim 65, wherein the active agent is a systemicallyactive therapeutic agent.
 69. The solid dosage form of claim 65, whereinthe active agent is a locally active therapeutic agent.
 70. The soliddosage form of claim 65, wherein said coating comprises a hydrophobicpolymer.
 71. The solid dosage form of claim 65, wherein said coating isan enteric coating.
 72. The solid dosage form of claim 65, wherein saidcoating comprises a hydrophilic material.
 73. The solid dosage form ofclaim 65, wherein said coating is a support platform.
 74. The soliddosage form of claim 73, wherein said support platform partially coatsthe compressed mixture.
 75. The solid dosage form of claim 65, wherein aportion of the active agent is in the coating.
 76. A tablet comprising:an excipient including microcrystalline cellulose in intimateassociation with 0.1% to 20% weight by weight SiO₂; an active agent; anda coating.
 77. The tablet of claim 76, wherein said coating comprises ahydrophobic polymer.
 78. The tablet of claim 76, wherein said coating isan enteric coating.
 79. The tablet of claim 76, wherein said coatingcomprises a hydrophilic material.
 80. The tablet of claim 76, whereinsaid coating is a support platform.
 81. The tablet of claim 80, whereinsaid support platform partially coats the tablet.
 82. The tablet ofclaim 76, wherein a portion of the active agent is in the coating.